TDP-43 modulates translation of specific mRNAs linked to neurodegenerative disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE111775 | GEO | 2018/10/08
REPOSITORIES: GEO
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Project description:To investigate how translation changed as a function of TDP-43 CR loss, mass spectrometry (MS) based approach was performed to monitor the dynamics of TDP-43-associated protein complexes in response to CR deletion using TDP-43 knockout HEK293 cells expressing strep tagged wild type TDP-43 (TDP-43WT) or TDP-43ΔCR mutant.
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Project description:The aim of this study is to understand the mechanisms of TDP-43 neurotoxicity. Here, we perform a RNA-Seq analysis in TDP-43 gain-of-fucntion (GOF) , TDP-43 loss-of-function and wild-type late pupae heads (73-90 hours APF) and perform TDP-43 GOF vs wild type and TDP-43 LOF vs wild-type differential expression analysis to show that both mechanisms presents defects in ecdysone receptor (ECR)-dependeint transcriptional program switching, and strongly deregulate expression from the neuronal microtubule associated protien Map205.
2013-01-22 | GSE42844 | GEO
Project description:The aim of this study is to understand the mechanisms of TDP-43 neurotoxicity. Here, we perform a RNA-Seq analysis in TDP-43 gain-of-fucntion (GOF) , TDP-43 loss-of-function and wild-type late pupae heads (73-90 hours APF) and perform TDP-43 GOF vs wild type and TDP-43 LOF vs wild-type differential expression analysis to show that both mechanisms presents defects in ecdysone receptor (ECR)-dependeint transcriptional program switching, and strongly deregulate expression from the neuronal microtubule associated protien Map205. RNA-seq was performed in two wild-type D.melanogaster biological replicates (Canton S, w1118 ), four biological replicates for TDP-43 (LOF) with two distinct genotypes (dTDP-43Δ142/Df(2R)106,dTDP-43Δ23/Δ142 ) and two TDP-43 GOF biological replicates (act5c>dTDP-43 ).
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Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer.
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Project description:The TAR DNA Binding Protein (TDP-43) has been implicated in the pathogenesis of human neurodegenerative diseases and exhibits hallmark neuropathology in amyotrophic lateral sclerosis (ALS). Here, we explore its tractability as a plasma biomarker of disease and describe its localization and possible functions in the cytosol of platelets. Novel TDP-43 immunoassays were developed on three different technical platforms and qualified for specificity, signal-noise ratio, detection range, variation, spike recovery and dilution linearity in human plasma samples. Fractionation studies revealed that >95% of plasma TDP-43 protein [RL1] was located within the platelet cytosol, together with numerous RNAs. Platelet-derived TDP-43 exhibits TDP-43 proteoforms detected in neurodegenerative diseases, TARDBP RNA splice variants and TDP-43 RNA targets found in the central nervous system (CNS). We propose that TDP-43 serves similar functional roles in platelets and synapses, suggesting that the study of platelet TDP-43 might provide a window into TDP-43 proteinopathies within the CNS. The restricted compartmentalization of plasma TDP-43 in platelets provides a highly concentrated substrate for further biochemical analyses. Moreover, our results suggest that current plasma biobanking protocols are subject to considerable heterogeneity in platelet recovery and measurements of TDP-43 in plasma.
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Project description:MicroRNAs (miRNAs) play important roles in a wide range of cellular processes. Aberrant regulation of miRNA genes contributes to human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs whose expression levels are regulated by TDP-43 using RNA-Seq coupled with siRNA-mediated knockdown approach. TDP-43 knocking down affected the expression of a number of miRNAs. Alterations in isomiR patterns and miRNA arm selection after TDP-43 knockdown suggest a role of TDP-43 in miRNA editing. We examined correlation of selected TDP-43 associated miRNAs and their candidate target genes in human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p expression. On the other hand, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Low expression of miR-500a-3p was associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Our experiments reveal that cancer-associated genes LIF and PAPPA may be targets of miR-500a-3p. Together with other studies, our work suggests that TDP-43-regulated miRNAs may play multi-facet roles in the pathogenesis of cancer. small RNA seq in SH-SY-5Y, SNB-19 and HT22 (TDP-43 siRNA VS Control siRNA)
2016-08-02 | E-GEOD-85065 | biostudies-arrayexpress
Project description:Mutation in TDP-43 is causative to amyotrophic lateral sclerosis (ALS). TDP-43 is a multifunctional ribonucleoprotein and is reproted to regulate thousands of genes in neurons, but how astrocytes contribute to TDP-43 pathogenesis is not known. This study examined how mutant TDP-43 in astrocytes kills motor neurons and causes ALS phenotypes. Primary astrocytes were isolated from transgenic rats expressing mutant TDP-43 or from control rats without mutant TDP-43 expression. Cultured astrocytes were induced to express mutant human TDP-43 and their gene expression profiles were determined by microarray assays. Microarray analysis revealed that hundreds of genes were altered in astrocytes in response to mutant TDP-43 expression.
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Project description:Mutation in TDP-43 is causative to amyotrophic lateral sclerosis (ALS). TDP-43 is a multifunctional ribonucleoprotein and is reproted to regulate thousands of genes in neurons, but how astrocytes contribute to TDP-43 pathogenesis is not known. This study examined how mutant TDP-43 in astrocytes kills motor neurons and causes ALS phenotypes. Primary astrocytes were isolated from transgenic rats expressing mutant TDP-43 or from control rats without mutant TDP-43 expression. Cultured astrocytes were induced to express mutant human TDP-43 and their gene expression profiles were determined by microarray assays. Microarray analysis revealed that hundreds of genes were altered in astrocytes in response to mutant TDP-43 expression. As mutant TDP-43 transgene is under the control of tetracycline-regulated pomoter elements (TRE), mutant TDP-43 expression is subjected to Doxycline regulation. Astrocytes isolated from GFAP-tTA/TRE-TDP43M337V rats were desiginated as M337V groups and astrocytes isolated from GFAP-tTA single transgenic rats were desiginated as tTA control groups. Total RNA was isolated from cultured astrocytes at varying times (3, 4, or 6 days after Dox withdrawal) after mutant TDP-43 was induced in astrocytes. Upon mutant TDP-43 induction in astroyctes, gene expression profiles in astroyctes were determined by Illumina Direct Hybridization Assay and compared between tTA and M337V groups at the varying time points of mutant TDP-43 induction.
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Project description:TDP-43 is an important RNA binding protein. To better understand its binding targets in human neurons, we performed TDP-43 iCLIP on SHSY5Y cells.
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Project description:TDP-43 is an RNA/DNA-binding protein implicated in transcriptional repression and mRNA processing. Inclusions of TDP-43 are hallmarks of frontotemporal dementias and amyotrophic lateral sclerosis. Besides aggregation of TDP-43, loss of nuclear localization is observed in disease. To identify relevant targets of TDP-43, we performed an expression profiling study. Thereby, histone deacetylase 6 (HDAC6) downregulation was discovered upon TDP-43 silencing on mRNA and protein level in human embryonic kidney HEK293E and neuronal SH-SY5Y cells. This was accompanied by accumulation of the major HDAC6 substrate, acetyl-tubulin. Expression of wild-type but neither RNA-binding- nor nuclear-localization-deficient TDP-43 restored HDAC6 expression. Moreover, TDP-43 bound specifically to HDAC6 mRNA arguing for a direct functional interaction. Importantly, in vivo validation in TDP-43 knockout Drosophila melanogaster also showed HDAC6 mRNA decrease. HDAC6 is necessary for protein aggregate formation and degradation. Indeed, downregulation of HDAC6 reduced aggregate formation and increased cytotoxicity of expanded poly-glutamine ataxin-3 in TDP-43 silenced cells. This was completely restored by co-transfection with HDAC6. In conclusion, loss of functional TDP-43 causes HDAC6 downregulation and might thereby contribute to pathogenesis.
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